2.1 Prostate Cancer
Prostate cancer represents the most commonly diagnosed cancer in males and is the second leading cause of cancer-related death in North American men. Prostate cancer is classified in four stages. Stage I prostate cancer is found in the prostate only and cannot be felt during a digital rectal exam nor is it visible by imaging. In stage II prostate cancer, the tumor has grown inside the prostate but has not extended beyond it, whereas in stage III, the cancer has spread outside the prostate, but to a minimal extent. Often, prostate cancer in stage III will have spread only to nearby tissues, such as the seminal vesicles. Finally, in stage IV, the cancer has spread outside the prostate to other tissues, such as the lymph nodes, bones, liver, and/or lungs.
Despite its high prevalence, treatment options for men having prostate cancer remain relatively limited and typically depend on the stage of the cancer. Treatment options include surgical treatments such as radical prostatectomy, in which the prostate is completely removed and radiation, applied through an external beam that directs the dose to the prostate from outside the body or via low-dose radioactive seeds that are implanted within the prostate to kill cancer cells locally. Anti-androgen hormone therapy also is used in the treatment of prostate cancer, either alone or in conjunction with surgery or radiation. Hormone therapy typically aims at blocking the pituitary from producing hormones that stimulate testosterone production by use of castration or administration of hormone analogs (e.g., luteinizing hormone-releasing hormone analogs) and requires that patients have injections of these hormone analogs for protracted periods (often for the rest of their lives). Finally, chemotherapeutic approaches have been used to treat advanced prostate cancer, usually as a last resort when other approaches have failed.
Although these treatments for prostate cancer can be somewhat effective in treating local tumors, each is accompanied by problematic or life-changing side effects. Radiation therapy can result in pain while urinating, localized hair loss, and impotence in those receiving treatment; surgery can cause permanent impotence and urinary incontinence; chemotherapy can result in a multitude of painful side effects, causing substantial morbidity; and hormone therapy can cause loss of sexual desire, impotence, nausea, and swelling of the breasts.
Moreover, none of these treatments are curative and prostate cancer often will progress despite surgical and hormonal-based therapies, resulting in so-called castration resistant prostate cancer (CRPC), which is characterized by progressive disease and rising levels of serum prostate-specific antigen (PSA).
Clinical disease manifestations of CRPC are commonly related to bone metastases and may include pain, pathologic fractures, and spinal cord compression, with local recurrences that may be associated with pelvic discomfort, renal dysfunction due to ureteral compression, bladder outlet obstruction, and sexual dysfunction (Damber et al. Lancet. 2008 May 17; 371(9625):1710-21). Further, while bone cancer is the predominant result of CRPC, patients may develop soft-tissue metastases in liver, lung, brain, and other organs (Damber et al. Lancet. 2008 May 17; 371(9625):1710-21; Petrylak et al. N Engl J Med. 2004 Oct. 7; 351(15):1513-20; Tannock et al. N Engl J Med. 2004 Oct. 7; 351(15):1502-12).
Patients with CRPC are minimally responsive to chemotherapy and the majority of patients die due to progressive prostate cancer within 20 months of initiating treatment (Tannock et al. J Clin Oncol. 1996 June; 14(6):1756-64). Indeed, in certain patients with CRPC, expectant management and symptom control are considered reasonable alternatives to chemotherapy (Basch et al. J Clin Oncol. 2007 Nov. 20; 25(33):5313-8).
Thus, prostate cancer can be a serious, progressive, disabling, and life-threatening disorder. CRPC, in particular, has with few adequate treatment options. It is clear that development of a therapy that can safely address a component of the pathogenesis of the disease would address a high unmet medical need. Text.
2.2 Benign Prostatic Hyperplasia
Benign prostatic hyperplasia (BPH) refers to the increase in size of the prostate in middle-aged and elderly men. BPH is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. When sufficiently large, the nodules compress the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra, which interferes with the normal flow of urine.
Symptoms of BPH include urinary hesitancy, frequent urination, dysuria (painful urination), increased risk of urinary tract infections and urinary retention. Although prostate specific antigen levels may be elevated in these patients because of increased organ volume and inflammation due to urinary tract infections, BPH is not considered to be a pre-malignant lesion.
BPH-associated adenomatous prostatic growth is believed to begin in men of approximately 30 years of age. An estimated 50% of men have histologic evidence of BPH by the time they reach 50 years old, and that number increases to 75% in men aged 80 and older.
Onset of BPH is believed to be caused by androgens such as testosterone and its metabolites and other hormones. Thus, current treatment options work by targeting these androgens. However, these treatments are not always curative, and patients often need to undergo invasive therapies such as are transurethral microwave thermotherapy and transurethral needle ablation, which deliver energy to the area of the prostate in an attempt create sufficient heat to cause cell death by necrosis in the prostate. Other patients require transurethral resection of prostate surgery, which involves removing part of the prostate through the urethra or other surgical approaches involving lasers.
Thus, there remains a need for effective non-invasive BPH therapies.